16/8/2018 Pharmacotherapy for generalized anxiety disorder in adults - UpToDate

Author: Alexander Bystritsky, MD, PhD

Section Editor: Murray B Stein, MD, MPH
Deputy Editor: Richard Hermann, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Jun 07, 2018.

INTRODUCTION — Generalized anxiety disorder (GAD) is characterized by excessive worry and anxiety
that are difficult to control, cause significant distress and impairment, and occur on more days than not for at
least six months [1].

GAD is a relatively common disorder, most often with onset during adulthood and a chronic course [2-5].
GAD can lead to significant impairments in role functioning, diminished quality of life, and high healthcare
costs [6,7]. The disorder can be effectively treated with medication, psychotherapy, or a combination of the
two modalities.

This topic addresses pharmacotherapy for GAD. The epidemiology, pathogenesis, clinical manifestations,
course, and diagnosis of GAD are described separately, as is psychotherapy for GAD. Anxiety disorders in
children and adolescents is also described separately. (See "Generalized anxiety disorder in adults:
Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and
"Psychotherapy for generalized anxiety disorder in adults" and "Anxiety disorders in children and
adolescents: Epidemiology, pathogenesis, clinical manifestations, and course" and "Pharmacotherapy for
anxiety disorders in children and adolescents" and "Psychotherapy for anxiety disorders in children and
adolescents".)

Complementary and alternative treatments for anxiety symptoms and disorders are also discussed
separately. (See "Complementary and alternative treatments for anxiety symptoms and disorders: Herbs
and medications" and "Complementary and alternative treatments for anxiety symptoms and disorders:
Physical, cognitive, and spiritual interventions".)

APPROACH TO TREATMENT — Our approach to selecting among treatments for generalized anxiety
disorder, including the use of pharmacotherapy and psychotherapy, is discussed separately. (See
"Approach to treating generalized anxiety disorder in adults".)

SEROTONERGIC REUPTAKE INHIBITORS (SRI) — Selective-serotonin reuptake inhibitors (SSRIs) and

serotonin-norepinephrine reuptake inhibitors (SNRIs) are efficacious in the treatment of generalized anxiety
disorder (GAD).

In cases of co-occurring GAD and depression, a common comorbidity, SSRIs can provide effective
treatment for both GAD and major depression. Other medications efficacious for GAD, eg, benzodiazepines
or pregabalin, are not effective treatments for depression.

Efficacy and side effects — There is a paucity of data available directly comparing different SRIs
(including SSRIs versus SNRIs) for GAD [8,9]. Trials have generally shown that all SRIs studied have the
same degree of effectiveness, ie, response rates of approximately 60 to 70 percent for the SRI, versus 40
percent for the placebo. The selection among SRIs can be customized to the patient based on the drug’s
side effect profile, drug-drug interactions, and/or patient treatment history/preference.

SSRIs — Selective serotonin reuptake inhibitors (SSRIs) that have been shown in randomized trials to
be efficacious for GAD include paroxetine [10-12], sertraline [13,14], citalopram, and escitalopram [15-17].
Uncontrolled trials and our clinical experience suggest other SSRIs (eg, fluoxetine and fluvoxamine) are
effective for GAD as well. A systematic review concluded that five patients with GAD would need to be
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treated with antidepressants (rather than placebo) for one patient to achieve a clinical response (ie, number
needed to treat = 5) [18].

As an example, the largest trial compared paroxetine at two fixed doses (20 and 40 mg/day) with placebo in
566 patients with GAD. After eight weeks of treatment, both doses of paroxetine resulted in a greater
reduction of anxiety symptoms than placebo (62 and 68 percent versus 46 percent, respectively). Rates of
remission (defined as ≤7 on the Hamilton Rating Scale for Anxiety) followed the same pattern: 30 and 36
percent for patients receiving 20 and 40 mg/day of paroxetine groups, respectively, compared with 20
percent for patients receiving placebo [11]. Randomized trials have shown SSRIs maintain efficacy for at
least six months [19]. Our clinical experience has been that they work for a much longer time in this chronic
condition.

SSRIs can produce side effects that interfere with the patient’s quality of life and medication adherence.
Thus, side effects need to be recognized and managed early in treatment. Individual SSRIs vary in their
side effect profile, but common side effects include sexual dysfunction, gastrointestinal abnormalities
(nausea and diarrhea), insomnia and withdrawal on discontinuation. SSRIs can cause drug interactions,
weight gain, and agitation and/or hyperactivation. A table compares side effects of antidepressants (table 1).
Management of SSRI side effects is described separately. (See "Selective serotonin reuptake inhibitors:
Pharmacology, administration, and side effects" and "Sexual dysfunction caused by selective serotonin
reuptake inhibitors (SSRIs): Management".)

SNRIs — Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit serotonin and norepinephrine

reuptake. Their efficacy and tolerability is comparable to SSRIs and the use follows the same general
guidelines. (See 'SSRIs' above.)

Venlafaxine (extended-release [XR]) [20-22] and duloxetine [23,24] have been shown to be efficacious in
randomized trials. As an example, venlafaxine XR at three fixed doses (37.5, 75, and 150 mg/day) has been
compared with placebo in a randomized trial of 541 outpatients with GAD [25]. The two higher doses (75
and 150 mg/day) demonstrated greater efficacy than placebo on all primary outcome measures at 8 and 24
weeks, while the lower dose (37.5 mg/day) did not. Longer-term trials have demonstrated efficacy for as
long as six months [23,26]. Both medications have been approved by the Food and Drug Administration in
the United States for GAD.

Common side effects of SNRIs are nausea, dizziness, insomnia, sedation, constipation, and sweating.
Venlafaxine may increase blood pressure, usually to a small extent. Rates of 3 to 7 percent have been seen
at doses of 100 to 300 mg/day, while the incidence of increased blood pressure was 13 percent at daily
doses >300 mg/day [27]. Typically, we ask patients with doses of venlafaxine of 150 mg per day or higher to
monitor their blood pressure. If blood pressure is increased in most cases, we either add or modify
antihypertensive treatment. (See "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology,
administration, and side effects".)

Administration — Therapeutic doses of SSRI and SNRIs are approximately the same as for the treatment
of depression. Starting doses from the lower end of the recommended range should be used to avoid initial
agitation (table 2). Time to onset of clinically meaningful action for an SRI varies by patient, but averages
approximately four weeks. The initial therapeutic dose should be continued for four to six weeks. If the
patient does not show a robust response, the SRI should be increased in one- to two-week increments until
sufficient improvement is seen or the maximum recommended or highest tolerated dose is reached (table
2). (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on
'Dose'.)

BUSPIRONE — The azapirone buspirone has been shown in clinical trials to reduce symptoms of anxiety in
patients with generalized anxiety disorder (GAD), offering similar efficacy to benzodiazepines without the
risk of dependence. Buspirone is thought to affect the serotonergic system via blockade of 5HT1A
autoreceptors.

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A meta-analysis of eight clinical trials in patients with GAD found buspirone to reduce anxiety symptoms
compared with placebo [28]. As an example, a clinical trial first treated 44 patients with GAD with lorazepam
(a benzodiazepine) for five weeks and then randomly assigned them to receive 15 mg/day of buspirone or
placebo, with a tapering off of the benzodiazepine [29]. After eight weeks, patients receiving buspirone
experienced reduced anxiety symptoms compared with placebo, and comparable to lorazepam. Buspirone
had fewer side effects compared with lorazepam.

Buspirone’s time to onset is longer than benzodiazepines’ and similar to the antidepressants’ average of
four weeks. In our experience, it has a weaker anxiolytic effect than benzodiazepines. These factors have
limited its use by psychiatrists largely to augmentation of selective serotonin reuptake inhibitors for GAD,
though it remains a popular treatment for GAD among primary care practitioners. Buspirone can be used as
monotherapy (in the absence of comorbid major depression) or for augmentation at doses of 10 to 60
mg/day (table 2). Typical side effects can include insomnia, agitation, and nausea.

PREGABALIN — Pregabalin has shown efficacy for generalized anxiety disorder (GAD) in comparison with
placebo in several randomized trials [30-35]. Pregabalin inhibits calcium currents via high-voltage-activated
channels containing the a2d-1 subunit, though the relationship of this mechanism to its efficacy in GAD is
not known. It was approved in 2006 for the treatment of anxiety in Europe [36,37]. Pregabalin is not
approved for treating GAD by the US Food and Drug Administration. The doses for pregabalin range from
50 to 300 mg, though many patients may need a total daily dose of greater than 150 mg (table 2). Side
effects include sedation and dizziness. Tolerance, withdrawal, and dependence are possible, but pregabalin
is generally better tolerated than benzodiazepines (table 2).

BENZODIAZEPINES — Benzodiazepines have been found to be efficacious in the treatment of generalized

anxiety disorder (GAD), generally leading to a reduction of emotional and somatic symptoms within minutes
to hours, depending on the specific medication (table 3) [38,39]. However, concerns about risks of
dependence and tolerance have contributed to a decline in their use [10,21]. A large observational study of
treatment of United States patients with GAD (without comorbidity) found that between 1989 to 1991 and
1996 benzodiazepine use declined and antidepressant use increased [40].

While benzodiazepines should be used with caution, and avoided in patients with a history of a substance
use disorder, their use need not be entirely avoided. They may be used for acute, maintenance, or long-
term treatment of GAD, either as monotherapy or, more commonly, as an adjunct to antidepressant
treatment. Benzodiazepines are most commonly used in GAD for acute management of anxiety and worry
during the period before selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine
reuptake inhibitors take effect. They can counteract the initial agitation often caused by the SSRI. Once the
patient responds to the SSRI, the benzodiazepine can be tapered off gradually. Antidepressants are
preferred over benzodiazepines when depression, a common comorbidity of GAD, is also present, because
antidepressants are effective treatments for both conditions. (See "Generalized anxiety disorder in adults:
Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

Patients with chronic GAD, minimal current depressive symptoms, and no history of a substance use
disorder are candidates for long-term, low-dose benzodiazepine treatment if antidepressants are ineffective
or poorly tolerated [41]. Some patients respond well to chronic treatment with benzodiazepines, do not
develop tolerance to their anxiolytic effects, which would require dose increase and experience only mild,
tolerable withdrawal symptoms when the medication is tapered off. Patients who develop rapid tolerance,
increase their doses against medical advice, or exhibit withdrawal symptoms between doses are not good
candidates for chronic benzodiazepine treatment. (See "Prescription drug misuse: Epidemiology,
prevention, identification, and management".)

Pharmacology — Benzodiazepines exert their principal pharmacodynamic effect via central nervous
system GABA receptors, potentiating the effects of endogenous GABA, the main inhibitory neurotransmitter.
GABA receptors are membrane-bound proteins divided into three subtypes, GABAA, GABAB, and GABAC
receptors. The GABAA receptors are composed of five subunits that together form the chloride channel,
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which primarily mediates neuronal excitability (seizures), rapid mood changes, clinical anxiety, and sleep.
GABAB receptors mediate memory, mood, and analgesia. The role of the GABAC receptors remains
unclear [42]. Flumazenil, a benzodiazepine antagonist, interacts with GABAA receptors [43] and is used
clinically to rapidly reverse the effects of benzodiazepine overdoses [44]. (See "Benzodiazepine poisoning
and withdrawal", section on 'Antidote (flumazenil)'.)

Although they share many class effects, unique properties of individual benzodiazepines have clinical
significance. These pharmacologic differences among the benzodiazepines include the rapidity of onset
(distributional half-life), persistence of active drug and/or metabolite in the body (elimination half-life), major
metabolic breakdown pathways (conjugation versus oxidation), and specific molecular structure (eg,
alprazolam has a unique triazole ring that may account for some difference in its clinical effects) [44]. These
differences are summarized in a table for the most widely used benzodiazepines, along with clinically
important pharmacologic characteristics related to the use and abuse of the benzodiazepines (table 3) [45].

Some benzodiazepines (alprazolam, diazepam, midazolam, triazolam) can lead to elevated methadone
peak levels and possibly other drug interactions via common cytochrome P450 3A4 oxidation pathways in
the liver. Oxazepam, lorazepam, and temazepam, which are metabolized primarily via conjugation and
cleared largely by the kidneys, have fewer P450 interactions and are better choices for patients taking
multiple medications, on methadone, or with compromised liver function [46].

Efficacy and side effects — A meta-analysis of 23 clinical trials found benzodiazepines to be efficacious in
the treatment of GAD compared with placebo. A metaanalysis of three clinical trials found the efficacy of
benzodiazepines to be comparable to the antidepressants. A limitation of benzodiazepine trials is that they
were conducted in patients diagnosed with the DSM-III definition of GAD, which differs significantly from the
contemporary DSM-5 diagnostic criteria. In our clinical experience, however, the efficacy of
benzodiazepines in patients diagnosed with DSM-5 GAD is evident within minutes of taking a more-rapid
onset benzodiazepine.

Side effects of benzodiazepines include impairment of psychomotor performance, amnesia, dependence

and withdrawal symptoms after long-term treatment, and rebound anxiety after short-term treatment [47].
Withdrawal and cognitive or learning impairment are more likely for persons taking higher doses.

Persistence of a benzodiazepine (or an active metabolite) in the body governs the timing of withdrawal
onset in patients who have used benzodiazepines every day for prolonged periods. Benzodiazepines with
shorter elimination half-lives (eg, alprazolam, lorazepam, and oxazepam) are more likely to produce acute
withdrawal on abrupt cessation after prolonged use. Benzodiazepines with longer elimination half-lives (eg,
clorazepate, diazepam, flurazepam, prazepam, and clonazepam) usually produce more delayed and
somewhat attenuated withdrawal symptoms.

Administration — Benzodiazepines are generally started at a low dose and titrated up as needed based
on response. As examples:

● Clonazepam can be started at 0.25 to 0.5 mg orally once or twice daily and titrated up to 1 mg two or
three times daily as needed.

● Diazepam can be started at 2.5 to 5 mg orally once or twice daily and titrated up to 10 mg two or three
times daily as needed.

● Lorazepam, a benzodiazepine with an intermediate onset of action and shorter half-life, can be
started at 0.5 to 1 mg orally three times daily and titrated up to 1.5 mg four times daily as needed.

A table provides information on benzodiazepines’ dosing, comparative potency, onset, metabolism, and
elimination half-life (table 3).

Tapering off benzodiazepines is usually done very slowly, at approximately a 10 percent dose reduction per
one to two weeks, if circumstances allow. The prescriber should monitor the patient for symptoms of
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benzodiazepine withdrawal or relapse of GAD and slow the rate of dose reduction accordingly. Early signs
of withdrawal include anxiety, dysphoria, and tremor; advanced manifestations include perceptual
disturbances, psychosis, and seizures. (See "Benzodiazepine poisoning and withdrawal".)

OTHER MEDICATIONS — A significant proportion of generalized anxiety disorder (GAD) patients fail to
improve or have residual symptoms in response to multiple trials of the medications above [10,21]. Other
medications have been used as monotherapy or augmenting agents for treatment-resistant GAD despite
variable levels of supporting evidence [48]. These include other antidepressants, atypical antipsychotics,
anticonvulsants, and hydroxyzine. Dosing and characteristics of medications for GAD are provided in a
table (table 2). (See "Approach to treating generalized anxiety disorder in adults", section on 'Options for
medication resistance'.)

Other antidepressants — Imipramine, a tricyclic antidepressant (TCA), has been shown to be efficacious
in treatment of patients with generalized anxiety disorder, including those without comorbid depression or
panic disorder (table 2) [18]. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine
reuptake inhibitors (SNRIs) are generally preferred over TCAs because the latter have an increased risk of
cardiotoxicity in overdose and less acceptable tolerability profiles [49]. (See "Tricyclic and tetracyclic drugs:
Pharmacology, administration, and side effects".)

In our clinical experience, mirtazapine, a sedating antidepressant, may be useful in the treatment of
refractory anxiety with insomnia. Sedation and weight gain are two prominent side effects of this agent.
Clinical trials on the use of mirtazapine in GAD are insufficient to determine efficacy; the US Food and Drug
Administration has not approved mirtazapine for GAD [50].

Clinical trials have found vilazodone, a selective serotonin reuptake inhibitor and a 5-HT1A receptor partial
agonist, to be as efficacious as other SRIs in GAD [51,52]; in our clinical experience vilazodone has no
unique advantages compared with other SSRIs. Vortioxetine has shown mixed results compared with
placebo in clinical trials for GAD [52,53].

Antipsychotic medications — Another potential pharmacologic treatment strategy for treatment resistant
GAD involves the use of second-generation antipsychotic medication. Several randomized clinical trials
support the use of atypical neuroleptics in GAD, either as part of an augmentation strategy or as single
agents [54]. Quetiapine has been used for GAD, but has not been approved for the disorder by the US Food
and Drug Administration.

Adverse side effects associated with second generation antipsychotics include sedation, extrapyramidal
symptoms, and tardive dyskinesia (TD) (table 1). Other side effects associated mainly with second-
generation antipsychotics include weight gain and elevation of glucose and lipid levels. Because of the
likelihood of these types of adverse effects, atypical antipsychotics should be considered (usually
adjunctively to an SSRI or SNRI) for treatment resistant GAD after safer alternatives have been exhausted.
(See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side
effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects"
and "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis".)

Anticonvulsants — Tiagabine has not been found to be superior to placebo for GAD in three randomized
trials [55]. There have been no clinical trials of gabapentin for GAD, which has been tested in other anxiety
disorders. (See "Pharmacotherapy for social anxiety disorder in adults" and "Antiseizure drugs: Mechanism
of action, pharmacology, and adverse effects".)

Hydroxyzine — In a meta-analysis of five trials with 884 patients, hydroxyzine appeared efficacious for
GAD, though the analysis suggested a high risk of bias [56]. Hydroxyzine was found to be more sedating
than benzodiazepines and buspirone, and thus potentially useful for treating insomnia associated with GAD.
Other medications that have sedative effects could be used for this purpose, eg, eszopiclone [57], though
this has not been well studied.

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DURATION OF PHARMACOTHERAPY — If effective, antidepressant treatment for generalized anxiety

disorder (GAD) should be continued for at least 12 months rather than the 6 months supported by previous
research [58]. In a randomized trial, 136 patients with GAD who experienced reduced anxiety during six
months of treatment with venlafaxine extended-release (XR) were assigned to continue the medication or to
placebo for an additional six months [59]. Patients continuing venlafaxine XR had a much lower rate of
relapse during the second six months than patients receiving placebo (9.8 versus 53.7 percent). Incidence
rates of side effects during the second six months compared with the first six months were lower, did not
differ statistically between drug and placebo patients, and included no new side effects.

If the patient experiences a relapse following termination of an effective medication, the length of treatment
can be extended. After two relapses when tapering off the medication, ongoing maintenance treatment
should be considered.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Anxiety
disorders in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics”
and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on “patient info” and the keyword(s) of interest.)

● Basics topics (see "Patient education: Generalized anxiety disorder (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Our approach to selecting among treatments for generalized anxiety disorder, including the use of
pharmacotherapy and psychotherapy, is discussed separately. (See "Approach to treating generalized
anxiety disorder in adults".)

● This topic describes the efficacy, side effects, and administration of medications in the treatment of
generalized anxiety disorder (GAD). Cognitive behavioral therapy (CBT) for GAD is described
separately. (See "Psychotherapy for generalized anxiety disorder in adults", section on 'Cognitive-
behavioral therapy'.)

● Serotonergic reuptake inhibitors (SRIs), which include selective-serotonin reuptake inhibitors (SSRIs)
and serotonin-norepinephrine reuptake inhibitors (SNRIs), are efficacious in the treatment of GAD. No
one SRI (or subclass) has been found to be more efficacious than another; selection of a specific SRI is
typically customized to the patient based on the drug’s side effect profile, drug-drug interactions, and/or
patient treatment history/preference. (See 'Serotonergic reuptake inhibitors (SRI)' above.)

• As examples, treatment with paroxetine can be initiated at 20 mg per day. The dose can be titrated
up in increments of 10 mg, to a maximum of 40 mg/day.

• Extended-release venlafaxine has been shown to be effective at 75 and 150 mg/day and
duloxetine in doses of 20 to 90 mg per day (though duloxetine is typically started at 30 mg per
day).

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• Further dosing, side effects and other characteristic that differ across SRIs are described in tables
(table 1 and table 2).

● Patients who experience a good clinical response to an antidepressant for GAD should continue the
medication for at least 12 months to prevent relapse or recurrence. (See 'Duration of pharmacotherapy'
above.)

● Buspirone has been shown in clinical trials to reduce symptoms of anxiety in patients with GAD,
offering similar efficacy to benzodiazepines without the risk of physiologic dependence. Typical side
effects can include insomnia, agitation, and nausea. (See 'Buspirone' above.)

● Pregabalin has shown efficacy for GAD in several randomized trials in doses from 50 to 300 mg per
day (table 2). Side effects include sedation and dizziness. Tolerance, withdrawal, and dependence are
possible, but pregabalin is generally better tolerated than benzodiazepines. (See 'Pregabalin' above.)

● Benzodiazepines are efficacious for acute and long-term treatment of GAD, but should generally be
reserved for patients without a history of a substance use disorder. They may also be useful for acute
symptoms during the period before an SSRI takes effect, or as an adjunct for partial responders to
SSRIs or SNRIs (table 3). (See 'Benzodiazepines' above.)

As an example, clonazepam can be started at 0.25 to 0.5 mg orally one or two times daily and titrated
up to 1 mg two or three times daily based on response.

● For GAD patients with a co-occurring SUD, hydroxyzine (50 to 100 mg) or pregabalin are non-addictive
drugs with efficacy in GAD that can be used for insomnia. (See 'Pregabalin' above and 'Hydroxyzine'
above.)

● Other medication with efficacy in GAD include tricyclic antidepressants, benzodiazepines, mirtazapine,
and quetiapine. These drugs may have comparable efficacy to the SRIs, but are typically more poorly
tolerated due to adverse effects. (See 'Other medications' above.)

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